Il diabete o - SID Italia - Bonora... · 2016. 7. 26. · CME and Communication Activities: ABBOTT,...
Transcript of Il diabete o - SID Italia - Bonora... · 2016. 7. 26. · CME and Communication Activities: ABBOTT,...
Enzo Bonora
Endocrinologia, Diabetologia e Metabolismo
Università e Azienda Ospedaliera Universitaria
Integrata di Verona
Il diabete o
l’arte del mosaico
Virgilio – Volti e Immagini del PoetaMantova – Palazzo Te
16 Ottobre 2011-8 Gennaio 2012
Enzo Bonora – un mosaico di
trasparenti e lecite interazioni con
aziende dell’area del diabete
(Disclosure of Interest)
Advisory Boards: ABBOTT, BOEHRINGER INGELHEIM, ELI LILLY ITALIA, NOVARTIS FARMA, NOVO
NORDISK, ROCHE, TAKEDA ITALIA FARMACEUTICI
CME and Communication Activities: ABBOTT, ABIOGEN, A. MENARINI DIAGNOSTICS,
ASTRAZENECA, BAYER HEALTHCARE, BECTON DICKINSON, BOEHRINGER INGELHEIM,
BRISTOL-MYERS SQUIBB, ELI LILLY ITALIA, GSK, LABORATORI GUIDOTTI, LIFESCAN ITALIA,
MEDTRONIC, MERCK SERONO, MSD ITALIA, NEOPHARMED GENTILI, NOVARTIS FARMA, NOVO
NORDISK, PFIZER ITALIA, ROCHE, SANOFI-AVENTIS, SIGMA-TAU, TAKEDA ITALIA FARMACEUTICI
Research Grants: A. MENARINI DIAGNOSTICS, NOVO NORDISK, TAKEDA ITALIA FARMACEUTICI
Shareholder: NOVO NORDISK AG, PFIZER INC.
Speaking Bureau: ABBOTT, ASTRAZENECA, BOEHRINGER INGELHEIM, BRISTOL-MYERS
SQUIBB, ELI LILLY ITALIA, GSK, LABORATORI GUIDOTTI, MERCK SERONO, MSD ITALIA,
NEOPHARMED GENTILI, NOVARTIS FARMA, TAKEDA ITALIA FARMACEUTICI, SANOFI-AVENTIS,
SIGMA TAU
Diabete: un mosaico di malattie diverse
Secondario
Altri monogenici
MODY
LADA
Tipo 2
Tipo 1
Gestazionale
Diabete: un mosaico di geni coinvolti
Geni della disfunzione beta cellulare
• KCNJ11
• TCF7L2
• IGF2BP2
• WSF1
• SLC30A8
• CDC123
• TSPAN8
• KCNQ1
• MTNR1B
• HHEX
• CDKAL1
• CDKN2A/B
• HNF1B
• JAZF1
• GCKR
• ecc.
Geni dell’ insulino-resistenza
• ENPP1 (PC-1)
• PPARG
• ADAMTS9
Haplotype analysis of TCF7L2 polymorphisms and glucose
stimulated insulin secretion in newly-diagnosed T2DM
rs7901695 rs7903146 rs11196205 rs12255372 Haplotype
freqency
haplo.4 C T C G 0,0383
haplo.36 C T C T 0,3479
haplo.9 T C C G 0,0864
haplo.45 T C G G 0,4559
PROPORTIONAL CONTROL
0
100
200
300
400
500
600
5,5 8 11 15 20
Glycaemia (mmol/l)
Insu
lin S
ecre
tion
Rate
ISR
(pm
ol/m
in/m
2)
HAPLO.45
HAPLO.36
HAPLO.9
HAPLO.4
(Bonetti et al – JCE&M, 96: E389, 2011)
Sensibilità insulinica (M-clamp) nei soggetti diabetici del
VNDS in funzione della presenza o meno dell’allele di
rischio di PPARG2 e dell’allele di rischio di ADAMTS9
(Bonetti et al – submitted)
ADAMTS9
PPARG2
Hyperglycemia
LiverIncreased
endogenous glucose
production
Skeletal muscleImpaired glucose utilization
(transport, storage, oxidation)
Endocrine pancreasImpaired insulin secretion
Exaggerated glucagon secretion
Diabete: un mosaico di organi, tessuti, cellule coinvolti
nella patogenesi dell’iperglicemia
GutImpaired incretin effect
KidneyIncreased glucose reabsorption
BrainAbnormal metabolic control
Adipose tissueRelease of
diabetogenic molecules
(FFA, adipocytokines)
Relationship Between Fasting Glucose Levels
and Endogenous Glucose Output(DeFronzo RA - Diabetes 1988; 37:66787)
Fasting Glucose (mmol/l)
Fasting Glucose (mg/dl)
r=0.847
p<0.001Endogenous
Glu
cose
Outp
ut
(mg/kg.m
in)
0 100 200 300
10 155
1.5
2.0
2.5
3.0
3.5
4.0
Normals (n=73)
DMT2(n=77)
Normal range
T2DM
To
tal B
od
y G
luco
se U
pta
ke
(mg
/kg
• m
in)
CON0
7
6
5
4
3
2
1
0
P<0.01
12
Leg
Glu
co
se U
pta
ke
(mg
/kg
leg
wt p
er m
in)
Time (minutes)
1801401006040
8
4
0
(De Fronzo et al; J Clin Invest 1979 and 1985)
Whole Body and Muscle Insulin Resistance
in T2DM
0
4
8
12
16
-200 -300 -400 -500 -600 -700 -800 -900 -1000 -1100 >1100
Frequency Distribution of M-clamp in Subjects with Newly-diagnosed T2DM
M-clamp (µmol/min·m2 BSA)
%
No insulin resistance
Threshold of insulin resistance = upper limit of bottom quintile of M-clamp in 515 non-obese healthy subjects
Loss of First-Phase Insulin Secretion after
i.v. Glucose in T2DM(Ward WK et al; Diabetes Care 7:491, 1984)
Type 2 diabetes
–30 0 30 60 90 120
Normal
120
100
80
60
40
20
0
Time (minutes)
Pla
sm
a in
su
lin
(µ
U/m
l) 20 g
glucose
100
200
300
400
500
00 1 2 3 4 5
M-low (mg/kg EMBS per min)
AIR
(
U/m
L)
(Weyer C et al; J Clin Invest 104:787, 1999)
Changes in Insulin Secretion and Sensitivity are
Associated to the Development of T2DM
NGTNGT
IGT
DM
NGT - Non converters to
T2DM
NGT - Converters to T2DM
0
5
10
15
20
-0.8 -1.3 -1.8 -2.3 -2.8 -3.3 -3.8 -4.3 -4.8 >4.8
Frequency Distribution of -Index in Subjects with Newly-Diagnosed T2DM
-index (log units)
%
No -cell defect
Threshold of β-cell defect = upper limit of bottom quintile of β-index in 125 non-obese healthy subjects
Fasting p
lasm
a insulin
(m
U/L
)
Age (years)
0
250
500
750
1000
1250
1500
1750
0 6 12 18 24
A Proof-of-Concept from Mother Nature:
A Girl with LeprechaunismF
astin
g p
lasm
a g
lucose (m
g/d
l)
50
100
150
200
250
300
350
0
Insulin
Glucose
(Deng et al; Diabetes 53: 624, 2004)
52% -cells
48% β-cells
P <0.01
T2DM
Beta-Cells are Reduced and Alpha-Cells are
Increased in Human Pancreatic Islets from T2DM
35% -cells
65% β-cells
Nondiabetic
Plasma glucagon levels and endogenous
glucose production during an OGTT in T2DM
Time (min)
Pla
sm
a G
luca
go
n
(fm
ol/
L)
(Mitrakou A et al.; Diabetes 1990)
En
do
gen
ou
s G
luc
os
e P
rod
ucti
on
(µm
ol/
min
/kg
FF
M)
Time (min)
P<0.001 T2DM
vs Controls
P<0.001 T2DM
vs Controls
GLUT2 AMG Uptake
NGT T2DM NGT T2DM
AMG=methyl--D-[U14C]-glucopyranoside; CPM=counts per minute.
SGLT2
NGT T2DM0
2
6
8
0
500
1000
1500
2000
No
rma
lized
Glu
co
se
Tra
nsp
ort
er
Levels
CP
M
Increased Glucose Transporter Proteins
and Activity in Type 2 Diabetes
P<0.05
4
P<0.05
P<0.05
(Rahmoune et al, Diabetes 2005; 54:3427-3434)
Upper Hypothalamus Is Completely Unresponsive to an Oral
Glucose Load in Type 2 Diabetes. A functional MRI Study.
(Vidarsdottir S et al - Diabetes 56: 2547-2550, 2007)
water
glucose
water
glucose
Diabete
Sistema
immune
Tubo
digerente
Apparato
osteoarticolareCuteGonadi
Cervello
Diabete: un mosaico di danni d’organo
Prevalence of macrovascular complications
at time of diagnosis of T2DM(Verona Newly Diagnosed Diabetes Study; unpublished)
0
10
20
30
40
CHD Carotid
PlaquesFemoral
Plaques
Abnormal
ABI
%
Prevalence of microvascular complications
at time of diagnosis of T2DM
Retinopathy Nephropathy Autonomic
Neuropathy
0
10
20
30
40
%
(Verona Newly Diagnosed Diabetes Study; unpublished)
Prevalence of micro- and/or macrovascular
complications t time of diagnosis of T2DM(Verona Newly Diagnosed Diabetes Study; unpublished)
0
10
20
30
40
None Micro
onlyMacro
only
Micro
&
Macro
%
Diabete: un mosaico di alterazioni ancillari che contribuiscono alle complicanze e all’outcome
Obesità centrale &
disregolazione adiposa (adiposite)
disfunzione
endotelialeipertensione
dislipidemia
aterogenainfiammazione
steatosi
epatica
stress
ossidativo
iperuricemia
glucotossicità
lipotossicità
trombofilia
00
2020
4040
6060
8080
100100
High BMI
or waist
Hypertension
(>140/90)Dyslipidemia
%%
Prevalence of “Non-Glycemic” CardiovascularRisk Factors in Subjects with T2DM
(Verona Diabetes Complications Study; Bonora et al, Diabet Med 21: 52, 2004)
Metabolic Syndrome predicts CVD in T2DM(Verona Diabetes Complications Study; Bonora et al, Diabetic Med 21: 52, 2004)
1.16-20.74.89Metabolic Syndrome(yes vs no)
1.03-1.361.18HbA1c (per unit)
1.01-2.641.63Smoking (yes vs no)
1.03-1.071.05Age (per year)
C.I.OR
n= 559; age 65 yr; duration 9 yr; follow-up 4.5 yr
CVD= cardiovascular death, nonfatal MI or stroke, angina, TIA, asymptomatic CHD,
carotid or peripheral atherosclerosis (echo-doppler)
Sex, duration, treatment and LDL concentration did not enter in the model
Insulin Resistance Predicts CVD in T2DM(Verona Diabetes Complications Study; Bonora et al, Diabetes Care 25: 1135, 2002)
N=627, follow-up 4,5 yr. Model including also sex, duration, BMI, hypertension, HbA1c.
00
0.50.5
11
1.51.5
22
2.5
OR
CVD= cardiovascular death, nonfatal MI or stroke, angina, TIA, asymptomatic CHD,
carotid or peripheral atherosclerosis (echo-doppler)
Age
1.02-1.06
p<0.001
Smoking
1.00-2.35
p=0.01
T-Chol/HDLChol
1.06-1.39
p<0.001
1.14-2.12
p<0.001
Ln(HOMA)
CRP Predicts CVD in Men with T2DM(Health Professional Study; Schulze et al, Diabetes Care 27: 889, 2004)
Data adjusted for age, life-style factors, hypertension, cholesterol, BMI
N= 746; follow-up 5 years
0
1
2
3
I II III IV
RR
CRP quartiles
VCAM-1 Predicts Mortality in T2DM(Stehouwer et al; Diabetes 51:1157, 2002)
n=328; follow-up 9 yearsData adjusted for age, sex, duration, prior CVD, UAE, BMI, SBP, cholesterol, HbA1c
RR
VCAM-1 Tertiles
0
0.5
1
1.5
2
2.5
I II III
Fibrinogen Predicts CVD Mortality in T2DM(Bruno et al; Diabetologia 48:427, 2005)
n=1565; follow-up 11 yearsAdjusted for age, sex, HbA1c, LDL, HDL-C ratio, hypertension, smoking, baseline CHD
RR
Fibrinogen (g/l)
0
0,5
1
1,5
2
<3.0 3.0-3.49 3.5-4.1 >4.1
n= 2726; mean follow-up: 4.7 years
Serum Uric Acid Independently Predicts CVD Mortality in T2DM
(Zoppini et al; Diabetes Care 32: 1716-1720, 2009)
Ultrasonography-Diagnosed NAFLD is an
Independent Predictor of CVD in T2DMTargher G et al – Diabetes 2005; 12: 3541-3546
Variable Model 1 Model 2 Model 3
Age
(per 10 yr)
1.13
(1.07-1.14)
1.13
(1.07-1.14)
1.12
(1.06-1.14)
Sex
(M vs F)
1.48
(1.1-2.0)
1.46
(1.2-1.9)
1.46
(1.2-1.9)
Smoking
(yes vs. no)
1.42
(1.1-2.0)
1.40
(1.1-1.9)
1.40
(1.1-1.9)
NAFLD
(yes vs. no)
1.90
(1.4-2.2)
1.84
(1.4-2.1)
1.53
(1.1-1.7)
N=744, follow-up 5 yrs
Model 1: age and sex
Model 2: + smoking history, diabetes duration, HbA1C, LDL cholesterol, GGT levels, and use
of medications (i.e., hypoglycemic, antihypertensive, lipid-lowering, or antiplatelet drugs)
Model 3: + metabolic syndrome
Liver steatosis is an
independent risk
factor of CVD
Targher G, Day C, Bonora E
New Engl J Med 2010;
363:1341-1350
Chronic inflammation
Thrombophilia
Atherogenic Dyslipidemia
Dysglycemia
Insulin Resistance
Diabete: le tessere del mosaico dei parametri di
laboratorio, esami strumentali e visite di consulenza
HbA1c
Glicemia
Profilo
lipidico
Uricemia
Chetonuria
C-peptide
Ab-GADCreatinina Microalbuminuria
ECG
Ecodoppler
TSA
Ecodoppler
AAII
Ecografia
addome
Test
autonomici
Visita
oculistica
Diabete: un mosaico di parametri
glicemici da correggere
Elevata glicemia media
giornaliera
Iperglicemia
a digiuno
Elevata HbA1c
Esagerato picco glicemico
post-prandiale
Iperglicemia
post-prandialeEccessiva
Variabilità
glicemica
Ipoglicemia
0
10
20
30
40
Good Good Fair Fair Poor Poor
Glycemic Phenotypes in Treated T2DM(Bonora et al, Diabetologia 49:846, 2006; n=3284)
Satisf. Exagg. Satisf. Exagg. Satisf. Exagg.
Pre-prandial
Post-prandial
%
Mean Pre-prandial: good=<110; fair=110-160; poor >160 mg/dl
Mean Post-prandial: satisfactory=<40; exaggerated 40 mg/dl
HRs PPG T3 vs. T1-2
men 2.13
women 8.39
After adjusting for HbA1c
and other confounders
Post-Prandial Glucose and CVD in T2DM(Cavalot et al; JCEM 91: 813, 2006)
Independent predictors
Fasting glucose no
HbA1c no
Post-prandial glucose yes
HRs PPG T3 vs. T1-2
men 2.19
women 5.69
After adjusting for FBG
and other confouders
>18.4%
11.2-18.4%
<11.2%
IIIII
0 1 2 3 4 5follow-up (years)
_
_
_
_
_
_
_
0.7
0.75
0.8
0.85
0.9
0.95
1
Surv
iva
l pro
babili
ty
Cardiovascular Mortality in Elderly Patients with
Type 2 Diabetes Stratified According to
Variability of Fasting Plasma Glucose (CV-FPG)(Verona Diabetes Study; Muggeo et al, Circulation 1997)
VADT - Predictors of CVD Death
VariableHazard
Ratio
P
Value
Prior CVD event 3.116 0.0001
Age (per 10 yr) 2.090 <.0001
HDL (per 10 mg) 0.699 0.0079
Baseline HbA1c (per 1%) 1.213 0.0150
Severe Hypoglycemia 4.042 0.0076
(Duckworth et al – NEJM 2009; 360: 129-139)
Diabete: un mosaico di fenotipi clinici
fra cui districarsi
Media durata
Scompensato
Complicanze presenti
Media durata
Scompensato
Senza
Complicanze
Nuova diagnosi
Senza complicanze
Media durata
Compensato
Complicanze presenti
Nuova diagnosi
Complicanze presentiLunga durata
Compensato
Minime
Complicanze
Lunga durata
Scompensato
Complicanze
Severe
A New Paradigm in Diabetes Care:Customized HbA1c Targets
“Recruit” patient (newly diagnosed T2DM, middle age,
no prior CVD, any HbA1c)
HbA1c Target = <6.5%; “no mercy”
“Veteran” patient (long standing T2DM, older age,
no prior CVD, previously fairly controlled diabetes)
HbA1c target = 6.5-7.5%; “smooth decline”
“Injured Veteran” patient (long standing T2DM, prior CVD,
severely uncontrolled diabetes; “hyperglycemia addicts”
who need progressive adaptation to lower glucose levels?)
HbA1c target = 7.5-8.5%; “handle with care”
Diabete: un mosaico di farmaci
Anti-diabeticiMetformina
Sulfoniluree
Glinidi
Acarbosio
Glitazoni
Agonisti GLP-1R
Inibitori DPP-4
Insulina
IpolipidemizzantiStatine
Fibrati
Ezetimibe
Acido nicotinico
Anti-ipertensiviACE-inibitori
Sartani
Diuretici
Calcio-antagonisti
Beta-Bloccanti
Alfa-litici
Anti-aldosteronici
AltriASA
Ticlopidina
Clopidogrel
Allopurinolo
Gabapentin
Pregabalin
ecc. ecc. ecc.
Più sono i farmaci fra cui scegliere,
più facile è sbagliare e
più serve competenza ed esperienza
cioè….
più serve il Diabetologo!
Anti-diabetici a confronto: benefici ancillari
MET SU REP PIO DPP-4 Acarb GLP-1
BMI = =
TG () = = = =
HDL () = = = =
BP () = = = =
U-Alb - = = = = =
CPR = = = =
PAI-1 = = = =
ATS = = = = = =
CVD (?) (?)
Anti-diabetici a confronto: aspetti clinici
MET SU REP PIO DPP-4 Acarb GLP-1
Ipoglicemia + +
Vomito ++
Diarrea (+) +++ +
Fratture +
Edema +
Iniezioni +
N. sommin. + + ++ +++ (+)
Titolazione ++ + + +++ (+)
SMBG + +
Interazioni +++ + +
Diabete: un mosaico di professionisti che condividono la cura
Infermiere esperto
di diabete
Ortopedico
Diabetologo
Medico di Medicina
GeneraleNefrologo
Psicologo
Cardiologo
Chirurgo
Vascolare
Dietista
Neurologo
Oculista
Podologo
Diabete: un mosaico di centri diabetologici
Mortalità cardiovascolare
non afferenti p<0.001
afferenti
n=7,488; follow-up= 5 anni
0 1 2 3 4 575
80
85
90
95
100
anni
Sopra
vvis
suti (
%)
0 1 2 3 4 585
90
95
100
anni
Sopra
vvis
suti (
%)
Sopravvivenza dei diabetici assistiti presso il centro di
diabetologia rispetto ai non afferenti
(Verona Diabetes Study – Verlato G et al; Diabetes Care 19: 211, 1996)
Mortalità per tutte le
cause
afferenti
p<0.001
non afferenti
Diabete: un mosaico di spese per la cura
Anti-
diabetici
(6%)
Ricoveri
Ospedalieri
(57%)
Altri farmaci
(23%)
Esami di laboratorio e
strumentali
e visite mediche e
specialistiche
(14%)
Spesa media annua pro-capite circa € 2.750 (>75% complicanze)
Le tre emergenza sanitarie del mondo secondo l’Organizzazione Mondiale
della Sanità
Tubercolosi
Malaria
Diabete mellito
Risoluzione dell’ONU
n. 61/225 del 20 Dicembre 2006
(omissis) aumentare la consapevolezza pubblica sul
diabete e le relative complicanze, promuovere la
sua prevenzione e terapia, anche mediante
l’educazione e i mass media
Farmacisti
Comune
e altre
istituzioni
pubbliche
Università
Associazioni
dei pazienti
Azienda
Ospedaliera
e ULSSAziende
farmaceutiche
Istituzioni
private
Diabete: un mosaico di collaborazioni per
fronteggiare l’emergenza
Misurazioni
glicemiche in piazza
Conferenze
ai
cittadini
Sito web
Manifesti
Giornalino
quadrimestrale Opuscoli
e altro materiale
divulgativo
Interventi
TV e radio locali
Diabete: un mosaico di atti richiesti al
paziente (partecipazione alla cura)
Esami di
laboratorio
Attività
fisica
Dieta
Pastiglie e/o
iniezioni
Monitoraggio
glicemico Esami
strumentali
Visite
mediche
Lifelong Adherence Requested to
Diabetic Patients
During his/her life up to 100,000 times a person with
diabetes has to adhere to prescriptions, recommendations,
suggestions made by a doctor, a nurse, a dietician !!!
Diabete: un mosaico coi pezzi al posto
giusto…
….e non un
(in)cubo di Rubik
…. come un
puzzle in cui i
vari pezzi
combaciano
perfettamente
…
Fine e grazie